The present invention is directed to the field of ophthalmic pharmaceutical products, particularly products that may be applied directly to contact lenses. Products that are applied to contact lenses to clean, disinfect, enhance comfort, or otherwise treat the lenses are commonly referred to as “contact lens care products” or “CLC products”.
The invention is particularly directed to the provision of CLC products and other types of ophthalmic formulations containing one or more chemical agents to prevent contamination of the formulations by bacteria, fungi or other microbes. Such agents are referred to herein as “antimicrobial preservatives”. The invention is also directed to CLC products that contain one or more chemical agents to kill bacteria, fungi and other microorganisms that may accumulate on contact lenses when worn and handled by humans. Such agents are referred to herein as “disinfecting agents”. Both the antimicrobial preservatives and the disinfecting agents may be referred to herein as “biocides”.
The invention is broadly applicable to various types of ophthalmic pharmaceutical compositions, but it is particularly useful in the field of CLC products, especially products for treating soft contact lenses.
The terms “soft” and “hard” relative to contact lenses are generally associated with not only the relative hardness of the respective types of lenses, but also the type of polymeric material from which the lenses are formed. The term “soft” generally denotes a contact lens that is formed from a hydrophilic polymeric material, such as hydroxyethyl methacrylate or “HEMA”, while the term “hard” generally denotes a lens that is formed from a hydrophobic polymeric material, such as polymethylmethacrylate or “PMMA”. The surface chemistry and porosity of the hard and soft lenses is quite different. Soft lenses typically contain a large amount of water, are quite porous, and bear ionic charges on the exposed surfaces of the lenses, while hard lenses are considerably less porous and generally do not bear ionic surface charges.
The ionic surfaces and porous nature of soft contact lenses can lead to significant problems when the lenses come into contact with CLC products or other ophthalmic pharmaceutical compositions, due to chemical and/or physical interactions between the lenses and one or more components of the compositions. For example, cationic antimicrobial agents such as benzalkonium chloride, chlorhexidine, polyquaternium-1 and polyhexamethylene biguanide (“PHMB”) are known to have a propensity for binding with the surfaces of soft contact lenses and/or to become entrained in the porous lens matrix. This binding or entrainment can lead to the accumulation of a high concentration of biocide on the surface of the lens and/or within the lens matrix. This accumulation of biocide can lead to ocular irritation. Accordingly, CLC products and other ophthalmic products that can be applied directly to contact lenses must be formulated so as to avoid chemical or physical interactions between components of the products and the lenses.
A prior approach to solving or avoiding the above-described problems is described in U.S. Pat. No. 5,037,647 (Chowhan, et al.). The Chowhan, et al. '647 patent describes the use of a complexing agent (i.e., citrate) to prevent or reduce binding between the cationic antimicrobial agent polyquaternium-1 and soft contact lenses. The invention of the Chowhan, et al. '647 patent has been employed in OPTI-FREE® Rinsing, Disinfection and Storage Solution, which has been marketed by Alcon Laboratories, Inc. (Fort Worth, Tex., USA) for several years.
The inventors of the Chowhan, et al. '647 patent found that citrate could be utilized to prevent binding between the lenses and polyquaternium-1 by forming a soluble, reversible complex between the negatively charged citrate ions and the positively charged polyquaternium-1 molecules. However, it was also found that the formation of this polyquaternium-1/citrate complex reduced the antimicrobial activity of polyquaternium-1. Thus, anionic complexing agents can be utilized to prevent uptake of a cationic antimicrobial agent by contact lenses, but the resulting complex may inhibit the activity of the antimicrobial agent.
The chemical structure and properties of the antimicrobial agent being utilized is another factor that must be considered. Some antimicrobial agents exhibit both ionic and hydrophobic interactions with contact lens materials. The use of an ionic complexing agent to prevent uptake of such antimicrobial agents does not address the uptake that results from hydrophobic interactions. Thus, there is a need for a means of preventing uptake that results from hydrophobic interactions between antimicrobial agents and contact lens materials.
Despite the success of the invention described in the Chowhan, et al. '647 patent, there is a need for additional methods of formulating CLC products and other ophthalmic products to prevent binding or entrainment of components of the products on or in soft contact lenses. There is particularly a need for formulation technology that minimizes or eliminates biocide uptake in contact lenses without compromising the preservative or antimicrobial disinfection efficacy of the formulation, as well as a need for technology that is applicable to both cationic antimicrobial agents and other types of antimicrobial agents. The present invention is directed towards fulfilling these needs.
The present invention addresses the above-discussed needs by utilizing inorganic nanoparticles to act as a carrier or depot for the biocides utilized in CLC products, such as contact lens disinfecting solutions, as well as other types of ophthalmic compositions.
Synthetic smectite particulates with nanoparticle size dimensions have been previously utilized in pharmaceutical compositions. However, the concept of utilizing nanoparticles as agents to prevent biocide uptake in contact lens care has not been disclosed or suggested in the prior art.
U.S. Pat. No. 6,177,480 B1 (Tsuzuki, et al.) describes the use of a synthetic clay material (i.e., Laponite™) as a wetting agent for contact lenses and to assist in the removal of lipid deposits from contact lenses by surfactants.
U.S. Pat. No. 6,015,816 (Kostyniak, et al.) describes an improved method using colloid particles, such as smectite clay minerals, as a substrate for ligands having antimicrobial activity, so as to control microbial growth on a material. The ligands are strongly bound to the substrate surface and in this way the leachability of the antimicrobial agent is limited.
The following publications may be referred to for further background regarding the use of synthetic clay materials in pharmaceutical compositions:
Plaizier-Vercammen, “Rheological properties of Laponite XLG, a synthetic purified hectorite” Pharmazie, volume 47, page 856 (1992);
Grandolini, et al. “Intercalation compounds of hydrotalcite-like anionic clays with anti-inflammatory agents: I. Intercalation and in vitro release of ibuprofen International Journal of Pharmaceutics, volume 220, numbers 1-2, pages 23-32 (Jun. 4, 2001); and
U.S. Pat. No. 5,585,108 (Ruddy, et al.) “Formulations of Oral Gastrointestinal Therapeutic Agents in Combination with Pharmaceutically Acceptable Clays”.